Durvalumab and Tremelimumab With Platinum-based Chemotherapy in Intrahepatic Cholangiocarcinoma (ICC)

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

1. Histologically/cytologically confirmed diagnosed intrahepatic cholangiocarcinoma

2. Measurable disease based on RECIST 1.1 and have 1 or more radiologic featurescompatible with high risk (for resection and recurrence) but still consideredtechnically resectable per multidisciplinary tumor board (Surgical oncologist,radiologist and medical oncologist minimum) meeting. High risk features wouldinclude at least 1 of the following criteria-

• A large tumor (> 5cm) that would benefit from preoperative tumor shrinkage withsystemic therapy

• T1b-T4 tumor thought to be technically resectable

• Multifocal tumors/ a tumor with satellite lesions confined to the same lobe,thought to be technically resectable

• Suspicious or involved lymph nodes (N1) thought to be technically resectable

• Tumor with any vascular involvement/invasion considered technically resectable

• No extrahepatic metastases

3. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization (e.g.,Health Insurance Portability and Accountability Act in the US) obtained from thepatient/legal representative prior to performing any protocol-related procedures,including screening evaluations.

4. Adult male or female age >18 years at time of study entry

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

6. Life expectancy of > 6 months

7. Body weight >30 kg

8. Adequate normal organ and marrow function as defined below:

• Hemoglobin ≥ 10.0 g/dL

• Absolute neutrophil count (ANC ≥1.5 x 109/L (> 1500 per mm3)

• Platelet count ≥100 x 109/L (>75,000 per mm3)

• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will notapply to patients with confirmed Gilbert's syndrome (persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence ofhemolysis or hepatic pathology), who will be allowed only in consultation withthe sponsor.

• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal Measuredcreatinine clearance (CL) >60 mL/min or Calculated creatinine clearance CL>60mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hoururine collection for determination of creatinine clearance

9. Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if theyhave been amenorrhoeic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenoushormonal treatments, had radiation-induced menopause with last menses >1 yearago, had chemotherapy-induced menopause with last menses >1 year ago, orunderwent surgical sterilization (bilateral oophorectomy, bilateralsalpingectomy or hysterectomy).

10. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

11. Provide archival tumour tissue sample or newly obtained core or excisional biopsy ofa previously unirradiated tumour lesion. Tissue blocks are preferred but unstainedcut slides acceptable. In addition, should be open to undergoing a biopsy after atleast 2 cycles of therapy. Patients who do not undergo surgical resection after 4cycles will be advised to undergo another biopsy.

Exclusion Criteria:

1. Has had previous local (surgery, radiation, embolizing procedure) or systemictherapy for borderline resectable intrahepatic cholangiocarcinoma.

2. Participation in another clinical study with an investigational product during thelast 3 months.

3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.

4. Has ampullary cancer, extrahepatic cholangiocarcinoma or gall bladder cancer.

5. Patients with distant extrahepatic metastatic disease including distant (non-regional lymph nodes). NOTE: Regional lymph nodes depend on tumor site; forleft sided lesions, regional lymph nodes include inferior phrenic, hilar andgastrohepatic lymph nodes. For right sided lesions, regional lymph nodes includehilar periduodenal and peripancreatic lymph nodes.

6. Has any other histologic subtype except adenocarcinoma or mixed histology withadenocarcinoma/hepatocellular carcinoma.

7. Any unresolved toxicity NCI CTCAE Grade > 2 from previous anticancer therapy exceptfor alopecia, vitiligo and the laboratory values defined in the inclusion criteria.

8. Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the sponsor-investigator.

9. Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab or tremelimumab may be included only after consultationwith the sponsor-investigator. Any medical contraindication to the use ofplatinum-based doublet chemotherapy as judged by the treating physician.

10. . Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of study drugs.

11. History of allogenic organ transplantation.

12. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

13. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhoea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent.

14. History of active primary immunodeficiency.

15. History of another primary malignancy except for

• Malignancy treated with curative intent and with no known active disease ≥3 yearsbefore the first dose of IP and of low potential risk for recurrence

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease

• Adequately treated carcinoma in situ without evidence of disease

16. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),Patients with a past or resolved HBV infection (defined as the presence of hepatitisB core antibody [anti-HBc] and absence of HBsAg) are eligible. hepatitis C, Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA. Testing for HIV is not required at screening butpatients with known HIV disease will be excluded from the study.

17. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

18. Receipt of live attenuated vaccine within 30 days prior to the first dose of studydrug. NOTE: Patients, if enrolled, should not receive live vaccine whilst receivingstudy drug and up to 30 days after the last dose of study drug.

19. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or180 days afterthe last dose of durvalumab + tremelimumab combination therapy.

20. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

21. Prior randomization or treatment in a previous durvalumab and/or tremelimumabclinical study regardless of treatment arm assignment.

22. Has had severe hypersensitivity (≥ Grade 3) to anti -PD1/PDL1 or anti-CTLA4 therapyand/or any of their excipients in the past.

23. Patients who have received prior anti-PD-1, anti-PD-L1 or anti-CTLA-4:

• Must not have experienced a toxicity that led to permanent discontinuation ofprior immunotherapy. All AEs while receiving prior immunotherapy must havecompletely resolved or resolved to baseline prior to screening for this study.

• Must not have experienced a ≥Grade 3 immune related AE or an immune relatedneurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:Patients with endocrine AE of ≤Grade 2 are permitted to enrol if they arestably maintained on appropriate replacement therapy and are asymptomatic.

• Must not have required the use of additional immunosuppression other thancorticosteroids for the management of an AE, not have experienced recurrence ofan AE if re-challenged, and not currently require maintenance doses of > 10 mgprednisone or equivalent per day.

24. Judgment by the investigator that the patient is unsuitable to participate in thestudy and the patient is unlikely to comply with study procedures, restrictions andrequirements.